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New Developments in New Developments in Prostate Cancer: Prostate Cancer:

Localized Prostate CancerLocalized Prostate Cancer

New Developments in New Developments in Prostate Cancer: Prostate Cancer:

Localized Prostate CancerLocalized Prostate Cancer

David Sharp, MDAssistant ProfessorUrologic Oncology

Department of UrologyThe Ohio State University’s Wexner Medical Center

Incidence/ MortalityIncidence/ Mortality• 241,740 men will be diagnosed with

prostate cancer in 2012– 28,170 men will die

• Lifetime risk: 1 in 6 men diagnosed with prostate cancer during their lifetimeprostate cancer during their lifetime (8.6% of men will develop PCa between ages 50 and 70)

• Rates of incidence increased in late 80’s, early 90’s and have since leveled off

• Mortality has been decreasing in the US since that time

Age adjusted incidenceAge adjusted incidence

Age adjusted mortalityAge adjusted mortality

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Advances in Localized Prostate Cancer

Advances in Localized Prostate Cancer

• Outline various treatment options

• Trends in treatment

• Risk stratification• Risk stratification

• Active surveillance

• Focal Therapy

• Imaging advances

Options for TreatmentOptions for Treatment• Active surveillance• Definitive treatment

– Prostatectomy• Open, robotic

– Radiation• External Beam/ IMRTExternal Beam/ IMRT• Brachytherapy• Proton Beam/ Cyberknife

– Thermal • Cryotherapy• High intensity-frequency ultrasound

• Focal therapy– Cryotherapy, HIFU, Brachytherapy

Options for TreatmentOptions for Treatment• Active surveillance• Definitive treatment

– Prostatectomy• Open, robotic

– Radiation• External Beam/ IMRT

Optimal treatment strategy:- Long term

disease control- Minimal

treatment-related External Beam/ IMRT• Brachytherapy• Proton Beam/ Cyberknife

– Thermal • Cryotherapy• High intensity-frequency ultrasound

• Focal therapy– Cryotherapy, HIFU, Brachytherapy

morbidity- Maximum

preservation of quality of life

• Balance risk:

– Posed by the health and age of the patient

• Competing causes for death

Selecting TreatmentSelecting Treatment

• Competing causes for death

• Life expectancy

– Posed by the cancer and its treatment• Any treatment for prostate cancer associated

with potential decrement in quality of life

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Trends in Prostate Cancer TherapyTrends in Prostate Cancer TherapyLow risk Prostate Cancer

Zerbib, Zelefsky et al, Urology 72, Dec 2008.

ProstatectomyProstatectomy• Only treatment for localized prostate cancer

with Level 1 evidence confirming it improves:Overall survival, CSS, risk of mets, local progression

Bill-Axelson, Holmberg, Ruutu et al, NEJM 2005; 352: 1977-1984.

• Surgical advances and anatomic gunderstanding have allowed for decreased morbidity

Advantages of RP Disadvantages of RP

Long-term potential for cure Surgery

Full pathological information Hospitalization (1 night)

Relief of urinary obstruction Catheter

‘Easy’ to follow patients for recurrence

Recovery time

‘Peace of mind’ knowing the prostate is out

Incontinence

Incontinence and erectile dysfunction treatable

Erectile dysfunction

Prostatectomy in the U.S.Prostatectomy in the U.S.

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Stratification of riskStratification of risk• Pathologic stage and prognosis prediction

– Size, extent of the cancer (stage, biopsy results)

– Grade of tumor (Gleason grade)– PSA

• Probability of PSA recurrence after treatment most yreliably predicted– Might not predict for subsequent clinical events

• Local or distant recurrence• Cancer-specific and overall survival• Nomograms and algorithms combine these factors

and more

Stratification of riskStratification of risk

• Molecular markers

– PSA

– IL-6 and TGF-ß1

– Urine presence of PCA3

– TMPRSS2:ERG fusion transcripts

Active surveillanceActive surveillance

• For very low risk (subclinical) prostate cancers, the best therapy may be monitoring the disease

• Patients and physicians mayPatients and physicians may overestimate seriousness of low-risk cancers and lack confidence in accuracy of staging

• Short-term evidence supports the safety and efficacy of active surveillance

Watchful waiting vs. Active Surveillance

Watchful waiting vs. Active Surveillance

• Watchful waiting

– Suggests deferring intervention until symptoms develop

• Active surveillance

– Suggests close monitoring of

• PSA

• PSA change in time

• changes in digital rectal examination

• Subsequent biopsies

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•• Incidence of lowIncidence of low--risk disease is increasingrisk disease is increasing

Cooperberg Lubeck et al, J Urol 2003. Data from CaPSURE

•• Incidence of lower stage disease is increasingIncidence of lower stage disease is increasing

Cooperberg Lubeck et al, J Urol 2003. Data from CaPSURE


• Who’s a candidate

• Risk of delayed intervention

• Predicting progression

• Psychological impact





P h l i l i t• Psychological impact

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Who’s a candidateWho’s a candidate• Identify men who are at ‘good risk’

– Published criteria vary from institution to institution

– Criteria used at OSU• PSA ≤ 10 ng/ml

Gl ≤ 6• Gleason score ≤ 6• Clinical stage T1 to T2a• %positive cores <20%• Extent cancer in any core <33%• PSA prior to biopsy relatively stable

(PSAv <2)

Who’s a candidateWho’s a candidate

• Rebiopsy often critical

– Differences between biopsy and pathologic Gleason scores at prostatectomy reduced by extended biopsy

• Consider MRI of prostate to assist with clinical staging




• Predicting progression• Predicting progression


Risk of delayed interventionRisk of delayed intervention• Prognostic risk assessment not perfect

– One assumes some risk of disease progression while on active surveillance

• Can treatment be delayed until absolutely necessary without detriment to curability?– No differences in adverse pathologic features

or PSA recurrence for men with low risk PCa delaying RP up to 180 days

– No differences in men on active surveillance who eventually underwent RP median 26.5 mo later

Freedland, et al. J Urol. 2006, 175: 1298-1302.Warlick, et al. JNCI. 2006, 98: 355-357. .

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• Predicting progression• Predicting progression


Predicting progressionPredicting progression• ‘Window of curability’

– Identify early signs of disease progression so that window remains open

• What constitutes best criteria to monitor not fully determined

• What is the ‘trigger’ for treatment?– PSA velocity

– PSA doubling time

– Digital rectal examination

– Imaging






Psychological ImpactPsychological Impact

• Worry, anxiety, depression

• PSA ‘cripple’

• Untreated cancer in my bodyUntreated cancer in my body

• I’m doing nothing

• Frequent monitoring and rebiopsy worse than treatment

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Psycological ImpactPsycological Impact• If I’m going to end up being treated anyway, why

wait and worry

• Get it out and get it over with

• Approximately 30% of men received delayed pp y % ytherapy after median of 40 months on active surveillance

• With median follow-up of 42 months, 80% men remained on active surveillance with no prostate cancer-specific deaths or metastatic disease

Roemling, et al. Eur Urol. 2007, 99:1244-1250.Hardie, et al. BJU Int. 2005, 95: 956-960.

Psychological ImpactPsychological Impact

• Support groups:– After adjusting for ethnicity, age, and type

treatment, men attending support groups reported better health-related quality of life than men who did notmen who did not

– Though intended to provide emotional support, may produce a negative psychosocial response in men when believe pressured by group members to initiate aggressive treatment

• Rethinking prostate cancer– Chronic illness rather than instant killer

Outcomes for surveillanceOutcomes for surveillance• Data limited, but reported outcomes to date

are promising

• Difficult to study well due to:

– Slow growth of prostate cancer

– Time needed to develop metastasis, then death

– Dissimilar criteria for surveillance

– Dissimilar parameters monitored

– Dissimilar triggers to treatment

Outcomes for surveillanceOutcomes for surveillance

• Klotz, et al:– 300 patients– F/U 8 years– Overall survival 85%– Disease-specific survival 99.3%

S F i• San Francisco– 500 patients on surveillance– 24% received secondary treatment a median of 3

years (range 1-17 years) after initiating surveillance– 38% with increasing Gleason grading on rebiopsy

• Longer-term data with good end-points needed to confirm these results

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Role of focal therapyRole of focal therapy• Alternative to surgical removal or radiation to the

entire gland– Only treat the tumor itself “male lumpectomy”

• Focal therapy is attractive– Minimize morbidity- sexual and urinaryMinimize morbidity sexual and urinary

function• For focal therapy to be viable treatment option

– Must have accurate staging and grading– Precisely locate the cancer within the gland– Characterize the risk of the cancer to the

individual

Focal TherapyFocal Therapy

Potential energy sources:CryoablationHigh intensity frequency ultrasound (HIFU)Photodynamic therapyBrachytherapy or other radiation source

Barriers to focal therapyBarriers to focal therapy

• Precise staging and grading

• Multifocality

• Growth PatternGrowth Pattern

• Imaging

From Sartor, Hricak, Wheeler et al, Urology, 72, Dec 2008

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From Sartor, Hricak, Wheeler et al, Urology, 72, Dec 2008

• To improve localization of cancer

– Extended biopsy methods

• Increase over standard 10-12 core biopsy

• Many reports of cancer- high grade or with ECE- in RP specimen on side of pnegative biopsy

• Image guided (ultrsound or MRI) transrectal “saturation” or transperineal mapping biopsies

• Necessary over standard TRUS/ BX prior to focal therapy

Transperineal Template Mapping Biopsy (TTMB)

Transperineal Template Mapping Biopsy (TTMB)

• Performed in OR with template fixed against perineum and with ultrasound guidance- like brachytherapy

– Set number of cores from standardized locations– 20-90 cores– Pts at high risk for cancer despite negative transrectal

ultrasound-guided biopsy- TTMB >40% positive • McCracken et al-McCracken et al

– 100 pts requiring repeat prostate biopsy due to increasing PSA• 50 with transrectal saturation biopsy• 50 with transperineal template mapping biopsy (TTMB)• Cancer detection (46% vs 22%)• Complication rate 12 % for TTMB (retention or

hematuria) 22% for saturation biospy (UTI, rentention, or hematuria)

• Although more accurate, not commonly performed– resource intensive and expensive

Advances in prostate cancer imaging

Advances in prostate cancer imaging

• Ability to accurately image a cancer in the prostate is significantly limited- difficult to discern cancerous tissue from adjacent normal or BPH tissue.

• It is hoped that with advances in imaging• It is hoped that with advances in imaging tumors may be better identified within the prostate– Identify patients suitable for focal therapy– Plan and implement focal treatment– Monitor for cancer recurrence and

progression

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MRI and MRSIMRI and MRSI• Magnetic resonance imaging (MRI) and Magnetic

resonance spectroscopy imaging (MRSI) are undergoing continued evaluation

• Prostate cancer has proportionally lower levels of citrate and higher choline and creatinine that areas of BPH or normal prostate– deteced by MRSI

• Data suggests improvement in– Determining if organ confined

(Wang, Hricak, Kattan; Radiology 2006) – Assisting with surgical planning

(Hricak, Wang, Wei; Cancer 2004 )– Locating the cancer within the prostate – Finding anterior-based cancers missed on biopsy

• Very radiologist and institutiuon dependant and need specialized training in GU MRI interpretation. Inaccuracies still persist.

Focal Therapy ConclusionsFocal Therapy Conclusions

• Attractive potential option

• Although making progress with template biopsies and prostate imaging, more work is necessary before can provide full clinical h t i ti f t t th t icharacterization of prostate cancer that is

reliable

• Reasonable to explore in setting of clinical trials

Advanced Prostate CancerAdvanced Prostate CancerAdvanced Prostate CancerAdvanced Prostate Cancer

Ahmad Shabsigh, MDAssistant Professor

Department of UrologyThe Ohio State University’s Wexner Medical Center

Natural history of prostate cancerNatural history of prostate cancer

Local

Androgen Deprivation Chemotherapy

Local Therapy

RecurrenceMostly BCF

Death

Symptomatic

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Goals of Treatment of Advanced CaP

Goals of Treatment of Advanced CaP

• Prevent progression (bone mets)

• Prolong survival

I QOL• Improve QOL

• Minimize side effects

HistoricallyHistorically

• Androgen deprivation therapy.

– LHRH agonists (leuprolide, goserelin, and triptorelin)

G RH t t i t (D li )– GnRH receptor antagonist (Degarelix)

– First generation androgen receptor blockers (Bicalutamide)

• Second line hormonal manipulation: ADT withdrawal, ketoconazole, estrogens

Natural history of prostate cancerNatural history of prostate cancer

Local

Androgen Deprivation Chemotherapy

Therapy

RecurrenceMostly BCF

Death

Symptomatic

HistoricallyHistorically

• Mitoxantrone + Steroids: 1997

• Docetaxel was the first to show improved survival: 2004

• An artificial pre and post Docetaxel areas of interest

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Bone ProtectionBone Protection

• Zoledronic acid

• Denosumab

• Optimal schedule is not defined

– Poor dentation.

– SQ vs IV

– Cost

– Renal function

New Therapeutic AgentsNew Therapeutic Agents

• Immunotherapy (Sipuleucel-T)

• Bone targeting agents (Denosumab, Radium-223)

• Androgen pathway (Abiratoerone, MDV3100)

Integrated Data From 2 Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trials of Active Cellular

Immunotherapy With Sipuleucel-T in

Integrated Data From 2 Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trials of Active Cellular

Immunotherapy With Sipuleucel-T in py pAdvanced Prostate Cancer

py pAdvanced Prostate Cancer

Celestia S. Higano, MD; Paul F. Schellhammer, MD; Eric J. Small, MD; Patrick A. Burch, MD;

John Nemunaitis, MD; Lianng Yuh, PhD; Nicole Provost, PhD; and Mark W. Frohlich, MD

Sipuleucel-TSipuleucel-T

• Sipuleucel-T consists of autologous peripheral blood mononuclear cells, including antigen-presenting cells (APCs), which have been activated in vitro with a recombinant fusion protein (prostatic acid phosphatase) linked to granulocyte-macrophage colony–stimulating factor.

• Designed to stimulate an immune response against prostate cancer.

Higano et al. Cancer 2009

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Side EffectsSide Effects

AFFIRM: Phase III ofMDV3100 vs

Placebo in Post C C C

AFFIRM: Phase III ofMDV3100 vs

Placebo in Post C C CChemotherapy CRPCChemotherapy CRPC

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Study DesignStudy Design

atio

n

MDV3100

160 mg daily

(800)1199 pts

post Docetaxel

Ran

dom

iza

2:1

(800)

Placebo

(399)

Overall Survival

ASCO 2012

AFFIRM TrialAFFIRM Trial

• 156 Centers in 15 countries

• Performance status: 0-2

• 90% power to detect 24% in reduction of mortality

• Interim analysis at 520 events

ASCO 2012

50

60

70

80

90

100

MDV3100

18.4 months

0

10

20

30

40

0 2 4 6 8 10 12 14 16 18 20

Placebo13.6 months

HR = 0.631 (0.53, 0.75) p < 0.0001 37% reduction in mortality

ASCO 2012

Prednisone Plus Cabazitaxel Or Mitoxantrone For Metastatic

Castration-resistant Prostate Cancer Progressing AfterDocetaxel Treatment:

A Randomised Open-label Trial

Prednisone Plus Cabazitaxel Or Mitoxantrone For Metastatic

Castration-resistant Prostate Cancer Progressing AfterDocetaxel Treatment:

A Randomised Open-label TrialA Randomised Open-label TrialA Randomised Open-label Trial

Johann Sebastian de Bono, Stephane Oudard, Mustafa Ozguroglu, Steinbjørn Hansen, Jean-

Pascal Machiels, Ivo Kocak, GwenaëlleGravis,Istvan Bodrogi, Mary J Mackenzie, Liji Shen,

Martin Roessner, Sunil Gupta, A Oliver Sartor

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atio

n Cabazitaxel

(378)

105 ptscompleted the

755 pts

Ran

dom

iza (378) study

Mitoxantrone

(377)

46 ptscompleted the

study

De Bono, Lancet 2011

Overall SurvivalOverall Survival


Progression Free SurvivalProgression Free Survival


Denosumab And Bone-metastasis-free Survival In Men With Castration-

resistant Prostate Cancer: Results Of A Phase 3, Randomised, Placebo-

controlled Trial

Denosumab And Bone-metastasis-free Survival In Men With Castration-

resistant Prostate Cancer: Results Of A Phase 3, Randomised, Placebo-

controlled Trial

Matthew R Smith, Fred Saad, Robert Coleman, Neal Shore, Karim Fizazi, Bertrand Tombal, Kurt Miller, Paul Sieber, Lawrence Karsh,

Ronaldo Damião, Teuvo L Tammela, Blair Egerdie, Hendrik Van Poppel, Joseph Chin, Juan Morote, Francisco Gómez-Veiga, Tomasz Borkowski, Zhishen Ye, Amy Kupic, Roger Dansey, Carsten Goessl

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DenosumabDenosumab

Small et al, Lancet 2012

Inclusion CriteriaInclusion Criteria

• CRPC

• Total serum testosterone level of < 50 ng/dl

• High risk for development of bone metastasis

– PSA value ≥ 8 ng/ml within 3 months before randomization and/or PSA doubling time ≤ 10 months

Exclusion CriteriaExclusion Criteria

• Radiographically detectable bone metastasis.

• Any metastatic involvement of distal organs (LAP is ok).

• IV biphosphonate administration.

• Osteonecrosis/osteomyelitis of the jaw.

Development of Bone Metsor death

Development of Bone Metsor death

Decrease by 15%


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Abiraterone and Increased Survival in Metastatic Prostate

Cancer

Abiraterone and Increased Survival in Metastatic Prostate

CancerJohann S. de Bono, M.B., Ch.B., Ph.D., Christopher J. Logothetis, M.D., Arturo Molina, M.D., Karim Fizazi, M.D., Ph.D., Scott North, M.D., Luis Chu, M.D., Kim N. Chi, M.D., Robert J. Jones, M.D., Oscar B. Goodman, Jr., M.D., Ph.D., Fred

Saad, M.D., John N. Staffurth, M.D., Paul Mainwaring, M.D., M.B., B.S., Stephen Harland, M.D., Thomas W. Flaig, M.D., Thomas E. Hutson, D.O., Pharm.D., Tina

Cheng, M.D., Helen Patterson, M.D., John D. Hainsworth, M.D., Charles J. Ryan, M.D., Cora N. Sternberg, M.D., Susan L. Ellard, M.D., Aude Fléchon,

M.D., Ph.D., Mansoor Saleh, M.D., Mark Scholz, M.D., Eleni Efstathiou, M.D., Ph.D., Andrea Zivi, M.D., Diletta Bianchini, M.D., Yohann Loriot, M.D., Nicole Chieffo, M.B.A., Thian Kheoh, Ph.D., Christopher M. Haqq, M.D., Ph.D., and

Howard I. Scher, M.D.


n 2

:1

Daily AbirateroneAcetate 1000 mg, Prednisone 5 mg

(797) Overall

1195 pts post Docetaxel

Ra

nd

om

iza

tio

Daily Placebo, Prednisone 5 mg

(398)

Overall Survival (25% improvement;

HR 0.8)


De Bono, NEJM 2011

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Progression Free SurvivalProgression Free Survival

De Bono, NEJM 2011

Side EffectsSide Effects

Radium 223 Chloride

(ALSYMPCA t i l)

Radium 223 Chloride

(ALSYMPCA t i l)(ALSYMPCA trial)(ALSYMPCA trial)

Radium 223Radium 223

• Similar to Ca.

• Alpha particles

130 t• 130 center

• 19 countries

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Symptomatic CRPC Total ALP < 220 U/L vs ≥ tio

n

6 doses of Radium 223 (50 kBq/kg) at

least 4 weeks apart + best standard of care

>2 bone mets

No visceral mets

Post Docetaxel or unfit for Docetaxel

220 U/L vs ≥ 220 U/l

Biphosphonateuse

Prior Docetaxel Ra

nd

om

iza

2:1

Placebo + Best standard of care

N= 921


ASCO 2012

First Skeletal Related EventsFirst Skeletal Related Events

ASCO 2012

Advanced Prostate CancerConclusions

Advanced Prostate CancerConclusions

• Promising new agents with improvement in survival and quality of life

• Sequence of treatments is not clear

• Earlier use maybe better pending clinical trials

• Personalized care.

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